Thrombocytopenia in murine schistosomiasis is associated with platelet uptake by liver macrophages that have a distinct activation phenotype
Alongside their well-established role in hemostasis, platelets are key modulators of immune cell function. This is particularly the case for macrophages, as platelets can either promote or dampen macrophage activation in a context-specific manner. Whilst the role of platelets in modulating classical (M1) macrophage activation following bacterial challenge is relatively well understood, whether platelets control other macrophage responses is less clear. We investigated the role of platelets in type 2 inflammation using a mouse model of chronic schistosomiasis. Schistosome infection caused thrombocytopenia which was partially reversed after drug-induced parasite death. Reduced platelet levels in infection were coincident with impaired thrombopoietin production by hepatocytes, reflecting the extensive liver damage caused by parasite eggs. Infection also reduced the ploidy and size (but not number) of bone marrow megakaryocytes, which was associated with reduced platelet output. We show schistosome infection accelerated platelet clearance and promoted the formation of platelet-leukocyte aggregates. This was particularly the case for liver macrophages and monocytes. Phenotypic analysis shows that platelet-associated liver macrophages had a distinct activation phenotype that included elevated expression of the alternative (M2) activation marker RELM. Despite this, in vitro studies indicated that platelets do not directly promote macrophage alternative activation. Similarly, whilst in vivo pharmacological treatment with a TPO mimetic enhanced platelet numbers and platelet-leukocyte aggregates, this did not alter macrophage phenotype. Conversely, antibody-mediated depletion of platelets or use of platelet-deficient mice both led to extensive bleeding following infection which impacted host survival. Together, these data indicate that whilst platelets are essential to prevent excessive disease pathology in schistosomiasis, they have a more nuanced role in myeloid cell activation and type 2 immune responses Author SummaryPlatelets are the second most abundant blood cell and are best known for their role in stopping bleeding after blood vessel damage. More recent studies have revealed another important function of platelets is their ability to control immune cell activation. Here, we investigate the role of platelets in immune responses to schistosomes, parasitic worms that cause the disease schistosomiasis that affects hundreds of millions worldwide. Schistosome worms live in our blood vessels and release large numbers of eggs that must exit the blood and move through our tissues to exit the body for onward transmission. However, a large number of eggs become trapped in different organs causing inflammation and disease pathology. We find that schistosome infection reduces the numbers of platelets in the blood of laboratory mice. Platelets are taken up by liver macrophages, and whilst these macrophages have a distinct activation profile compared to other cells, platelets themselves do not cause these changes. However, platelets are essential to survive schistosomiasis due to excessive bleeding in their absence. Together, this work shows that platelets are key to surviving schistosome infection but this reflects more their role in preventing bleeding rather than controlling immune cell function.